Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor

ABSTRACT

An oral solid dosage form includes a therapeutically effective amount of an NSAID and a proton pump inhibitor in an amount effective to inhibit or prevent gastrointestinal side effects normally associated with the NSAID. Also disclosed is a method of treating a human patient in need of antiinflammatory, analgesic and/or antipyretic therapy, comprising orally administering to the patient an oral pharmaceutical dosage form which includes a therapeutically effective amount of an NSAID and an amount of a proton pump inhibitor effective to substantially inhibit gastrointestinal side effects of the NSAID. The invention is further related to a method of prophylactically treating a human patient who is on a therapy known to have significant gastrointestinal side effects or is about to begin such a therapy, via concurrent administration of an NSAID and a proton pump inhibitor in a combination (single) oral dosage form.

FIELD OF THE INVENTION

The present invention is related to the combination of a non-steroidalantiinflammatory drug (“NSAID”) or one of its single enantiomers or saltof the NSAID, and a proton pump inhibitor or one of its singleenantiomers, or an alkaline salt of the proton pump inhibitor or one ofits single enantiomers, in a single oral pharmaceutical dosage form.

BACKGROUND

Although NSAIDs are often used for their antiinflammatory, analgesic,and/or antipyretic effects, it is well known that NSAIDs have thepotential to cause gastrointestinal (GI) bleeding through a variety ofmechanisms related to their topical and systemic effects. The GIbleeding may depend on the length of the treatment and on the particulardrug. This problem is important in cases where the therapy must becontinued for a long period of time. For example, osteoarthritis andrheumatoid arthritis in the elderly is often treated with long-termNSAID therapy, as chronic treatment is needed to control pain andinflammation and to improve quality of life.

Additionally it is well known that because of their side-effects on theGI tract, NSAIDs are invariably administered after meals or, generally,when the stomach is not empty. This pharmacological principle isconfirmed by the recommendations found in the labeling of thesemedications. Patients who have an ulcer or who are susceptible todeveloping ulcers are commonly advised to avoid taking NSAIDs for pain,inflammation, and/or fever.

Other measures which can be taken to decrease GI side affects associatedwith NSAID therapy is to coadminister an H₂ blocker e.g. ranitidine, ora prostaglandin analogue, e.g. misoprostol, with the NSAID. In fact, acombination tablet containing diclofenac sodium and misoprostol(Arthrotec®, Pharmacia Corp.) has had FDA approval since 1988.

There is a continuing need for analgesic medications able to providehigh efficacy pain relief while reducing the possibility of undesirableeffects. Non-steroidal anti-inflammatory drugs, including compounds suchas ibuprofen, ketoprofen and diclofenac, have anti-inflammatory actionsand are effective on pain associated with the release of prostaglandinsand other mediators of inflammation. For example, diclofenac andpharmaceutically acceptable salts thereof, e.g. diclofenac sodium, areconsidered to be extremely potent and effective as an analgesic andanti-inflammatory agent. Diclofenac is approved in the United States forthe long-term symptomatic treatnent of rheumatoid arthritis,osteoarthritis and ankylosing spondylitis. It is also considered to beuseful for the short-term treatment of acute musculoskeletal injury,acute shoulder pain, postoperative pain and dysmenorrhea. However,NSAIDs such as diclofenac produce side effects in about 20% of patientsthat require cessation of medication. Side effects include, for example,gastrointestinal bleeding and the abnormal elevation of liver enzymes.

Non-steroidal anti-inflammatory drugs (NSAIDs) exert most of theiranti-inflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase. Inhibition of COX-1 causes a number of side effectsincluding inhibition of platelet aggregation associated with disordersof coagulation, and gastrointestinal side effects with the possibilityof ulcerations and of hemorrhage. It is believed that thegastrointestinal side effects are due to a decrease in the biosynthesisof prostaglandins which are cytoprotective of the gastric mucosa.

A high incidence of side effects has historically been associated withchronic use of classic cyclooxygenase inhibitors, all of which are aboutequipotent for COX-1 or COX-2, or which are COX-1-selective. While renaltoxicity occurs, it usuallybecomes evident in patients who alreadyexhibit renal insufficiency (D. Kleinknecht, Sem. Nephrol. 15: 228,1995). By far, the most prevalent and morbid toxicity isgastrointestinal. Even with relatively nontoxic drugs such as piroxicam,up to 4% of patients experience gross bleeding and ulceration (M.J.S.Langman et al, Lancet 343: 1075, 1994). In the United States, it isestimated that some 2000 patients with rheumatoid arthritis and 20,000patients with osteoarthritis die each year due to gastrointestinal sideeffects related to the use of COX inhibitors. In the UK, about 30% ofthe annual 4000 peptic ulcer-related deaths are attributable to COXinhibitors (Scrip 2162, p.17). COX inhibitors cause gastrointestinal andrenal toxicity due to the inhibition of synthesis of homeostaticprostaglandins responsible for epithelial mucus production and renalblood flow, respectively.

The second form of cyclooxygenase, COX-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxins,hormones, cytokines and growth factors. It has been proposed that COX-2is mainly responsible for the pathological effects of prostaglandins,which arise when rapid induction of COX-2 occurs in response to suchagents as inflanmmatory agents, hormones, growth factors, and cytokines.Selective inhibitors of COX-2 have anti-inflammatory, antipyretic andanalgesic properties similar to those of a conventional non-steroidalanti-inflammatory drug (NSAID), but COX-2 inhibitors have been touted asproviding a reduced potential for gastrointestinal toxicity, among otherside effects. Nevertheless, experience with selective COX-2 inhibitorsis limited relative to experience with non-selective COX inhibitors(which non-selectively inhibit COX-1 and COX-2). Non-selective COXinhibitors are widely used, and it is expected that these drugs willcontinue to be widely used. Further, there has been recent suggestionsthat COX-2 inhibitors have serious but previously unrecognized sideeffects, including increased intraocular pressure and the risk ofglaucoma, as well as possible effects on the central nervous system.

For years, neutralization of gastric acid with antacids was the onlyrelief from the pain of ulcers. However, more recently, a class ofantisecretory agents that do not exhibit anticholinergic or H₂ histamineantagonistic properties, but that suppress gastric acid secretion by thespecific inhibition of the H⁺, K⁺—ATPase enzyme system at the secretorysurface of the gastric parietal cell, has been developed. These agents(hereinafter “proton pump inhibitors”) provide a more specific class ofinhibitors of gastric acid secretion in mammals and man by blocking thefinal step of acid production.

Generally, proton pump inhibitors, their single enantiomers or alkalinesalts thereof, are used for the prevention and treatment of gastric acidrelated diseases including, but not limited to, reflux esophagitis,gastritis, duodenitis, gastric ulcer and duodenal ulcer. These protonpump inhibitors may also be used in patients in intensive caresituations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent acid aspiration of gastric acid and toprevent and treat stress ulceration. Also, they may be useful in thetreatment of psoriasis as well as in the treatment of Helicobacterinfections and diseases related to these. Additionally, these protonpump inhibitors may be used for the treatment of other gastrointestinaldisorders where gastric acid inhibitory effect is desirable, such aspatients with Non Ulcer Dyspepsia, in patients with symptomaticgastro-esophageal reflux disease, in patients with gastrinomas, and inparticular in patients on NSAID therapy.

U.S. Pat. No. 5,817,338 (Bergstrand, et al.) describes multiple unittableted dosage forms of omeprazole, a proton pump inhibitorcommercially available for inhibiting gastric acid secretion in humans.Therein, it is suggested that omeprazole may be used for treatment ofother gastrointestinal disorders where gastric acid inhibitory effect isdesirable, e.g., in patients on NSAID therapy. However, this patent doesnot describe pharmaceutical formulations combining a proton pumpinhibitor such as omeprazole with an NSAID.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a method for the treatmentof pain, inflammation, and/or fever with the use of a NSAID without theundesirable stomach discomfort and other side effects typicallyassociated with NSAID therapy.

It is a further object of the invention to decrease the risk of thedevelopment and/or exacerbation of ulcers which may occur during NSAIDtherapy.

It is a further object of the invention to promote patient complianceand thereby increase efficacy of NSAID treatment in patients who arebeing chronically treated with NSAIDs.

It is a further object of the invention to provide prophylactictreatment to a human patient who is on NSAID therapy or is about tobegin NSAID therapy, in order to avoid or minimize gastrointestinalside-effects.

It is a further object of the invention to provide prophylactictreatment to a human patient who is on a therapy known to havesignificant gastrointestinal side effects or is about to begin such atherapy, in order to avoid or e such side effects.

It is a further object of the invention to provide cost effectivetherapy to decrease the risk of the development and/or exacerbation ofulcers which may occur during NSAID therapy.

In view of the above-mentioned objects and others, the invention isdirected to an oral solid dosage form comprising a therapeuticallyeffective amount of an NSAID and a proton pump inhibitor in an amounteffective to inhibit or prevent gastrointestinal side effects normallyassociated with the NSAID treatment.

The invention is further directed to a solid oral dosage form comprising

a) an NSAID (e.g. diclofenac or a pharmaceutically acceptable saltthereof) extended release tablet and

b) an enterically coated proton-pump inhibitor without a separatinglayer between the proton pump inhibitor and the enteric coat.

The invention is further directed to a (non-steroidal) antiinflammatory,analgesic, and antipyretic oral therapy which does not possess anysubstantial gastrointestinal side-effects, comprising an orallyadministrable dosage form comprising a therapeutically effective amountof an NSAID and an amount of a proton pump inhibitor effective tosubstantially inhibit gastrointestinal side effects of the NSAID,together with one or more pharmaceutically acceptable excipients.

The invention is further directed to a dosage form comprising atherapeutically effective amount of an NSAID and an amount of a protonpump inhibitor effective to substantially inhibit gastrointestinal sideeffects of the NSAID, wherein said proton pump inhibitor is coated witha material suitable to prevent contact of said proton pump inhibitorwith acidic gastric juice (e.g. an enteric coating). In preferredembodiments, the material is directly coated onto the proton pumpinhibitor without a separating layer between the material and the protonpump inhibitor.

The invention is further directed to the prophylactic treatment of ahuman patient who is on NSAID therapy or is about to begin NSAIDtherapy, via the concurrent administration of a proton pump inhibitor.

The invention is further directed to the prophylactic treatment of ahuman patient who is on a therapy known to have significantgastrointestinal side effects or is about to begin such a therapy, viathe concurrent administration of a proton pump inhibitor.

The invention is further related to a method of treating a human patientin need of antiinflammatory, analgesic and/or antipyretic therapy,comprising orally administering to the patient an oral pharmaceuticaldosage form comprising a therapeutically effective amount of an NSAIDand an amount of a proton pump inhibitor effective to substantiallyinhibit gastrointestinal side effects of the NSAID.

In certain preferred embodiments, the dosage form is an oral tabletcomprising the NSAID, the proton pump inhibitor, and one or morepharmaceutically acceptable excipients. In other preferred embodiments,the NSAID and the proton pump inhibitor comprise a mixture of tablets,powders, pellets, granules, or inert nonpareil beads coated with thedrugs, contained within a gelatin capsule.

The inventive formulations and methods described herein promote patientcompliance and thereby increase efficacy of NSAID treatment in patientswho are being chronically treated with NSAIDs. In other words, theinventive formulations increase the likelihood that a patient on NSAIDtherapy who is noncompliant due to gastrointestinal side effects, or whoforgets or refuses to take both medications separately will be moreaccepting of a single composition combining the NSAID and proton pumpinhibitor, particularly due to the avoidance of gastrointestinal sideeffects.

Proton pump inhibitors are known to be highly acid labile, and thereforeit is preferred that the proton pump inhibitor(s) contained in thedosage forms of the invention be protected from contact with acidicgastric juice.

In certain preferred embodiments, the proton pump inhibitor isomeprazole.

In certain preferred embodiments, the NSAID is diclofenac, morepreferably diclofenac sodium.

For purposes of this disclosure, all references to proton pumpinhibitors and NSAIDs include their single enantiomers and theirpharmaceutically acceptable salts.

For purposes of this disclosure, the phrase “substrates” is meant toencompass inert pharmaceutically acceptable beads, particles, granulesor pellets.

For purposes of this disclosure, the phrase “combination pharmaceutical”shall be understood to include any drug composition containing at leasttwo therapeutically active components of which at least one is anon-steroidal antiinflammatory drug. The term “pain-alleviating” shallbe understood herein to include the expressions “pain-suppressing” and“pain-inhibiting” as the invention is applicable to the alleviation ofexisting pain as well as the suppression or inhibition of pain whichwould otherwise ensue from an imminent pain-causing event.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of in vitro dissolution data which shows thedissolution profile of omeprazole from the initial formulation ofExample 1 and the formulation of Example 1 after exposure to acceleratedstorage conditions of 40° C. and 75% relative humidity for 2 weeks. Thedissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.

FIG. 2 is a graph of in vitro dissolution data which shows thedissolution profile of diclofenac from the initial formulation ofExample 1 and the formulation of Example 1 after exposure to acceleratedstorage conditions of 40° C. and 75% relative humidity for 2 weeks. Thedissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.

FIG. 3 is a graph of in vitro dissolution data which shows thedissolution profile of diclofenac from the initial formulation ofExample 2, the formulation of Example 2 after exposure to acceleratedstorage conditions of 40° C. and 75% relative humidity for 2 weeks andthe formulation of Example 2 after exposure to accelerated storageconditions of 40° C. and 75% relative humidity for 1 month. Thedissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.

FIG. 4 is a graph of in vitro dissolution data which shows thedissolution profile of omeprazole from the initial formulation ofExample 2, the formulation of Example 2 after exposure to acceleratedstorage conditions of 40° C. and 75% relative humidity for 2 weeks andthe formulation of Example 2 after exposure to accelerated storageconditions of 40° C. and 75% relative humidity for 1 month. Thedissolution medium is a 0.5 M Phosphate buffer at a pH 6.8.

DETAILED DESCRIPTION OF THE INVENTION

The term “NSAID,” as used herein, refers to any compound acting as anon-steroidal anti-inflammatory agent identifiable as such by one ofordinary skill in the art. For many years NSAIDs have been used fortreating pain and/or inflammation. “Treating” includes prophylaxis of aphysical and/or mental condition or amelioration or elimination of thedeveloped condition once it has been established, or alleviation of thecharacteristic symptoms of such condition. The term “pain” includes alltypes of pain. Pain includes, but is not limited to, chronic pains, suchas arthritis pain (e.g. pain associated with osteoarthritis andrheumatoid arthritis), neuropathic pain, and post-operative pain,chronic lower back pain, cluster headaches, herpes neuralgia, phantomlimb pain, central pain, dental pain, neuropathic pain, opioid-resistantpain, visceral pain, surgical pain, bone injury pain, pain during laborand delivery, pain resulting from bums, including sunburn, post partumpain, migraine, angina pain, and genitourinary tract-related painincluding cystitis, the term also refers to nociceptive pain ornociception.

The Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp1308-1309 provide well known examples of NSAIDs. The term NSAIDincludes, but is not limited to, the group consisting of salicylates,indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac,antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone,clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome,cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl,flufenamic acid, glaphenine, indoprofen, ketoprofen, meclofenamic acid,mefenamic acid, niflumic acid, phenacetin, salidifamides, sulindac,suprofen and tolmetin. The salicylates may include acetylsalicylic acid,sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylicacid, and sodium salicylate.

NSAIDs have been widely used in arthritis therapy for several years. Thefollowing references, hereby incorporated by reference, describe variousNSAIDs suitable for use in the invention described herein, and processesfor their manufacture: U.S. Pat. No. 3,558,690 to Sallmann and Pfister,(assigned to Ciba Geigy), issued 1971; U.S. Pat. No. 3,843,681 (assignedto American Home Products), issued 1974; U.S. Pat. No. 3,766,263 toGodfrey, (assigned to Reckitt and Colman) issued 1973; U.S. Pat. No.3,845,215 to Godfrey (assigned to Reckitt and Colman) issued 1974; U.S.Pat. No. 3,600,437 to Marshall (assigned to Eli Lilly), issued 1971;U.S. Pat. No. 3,228,831 to Nicholson and Adams, (assigned to Boots PureDrug), issued 1966; (U.S. Pat. No. 3,385,886 to Nicholson and Adams,(assigned to Boots Pure Drug) issued 1968; U.S. Pat. No. 3,161,654 toShen, (assigned to Merck & Co.), issued 1964; U.S. Pat. No. 3,904,682 toFried and Harrison, (assigned to Syntex), issued 1975; U.S. Pat. No.4,009,197 to Fried and Harrison, (assigned to Syntex), issued 1977; U.S.Pat. No. 3,591,584 to Lombardino (assigned to Pfizer) issued 1971; U.S.Pat. No. 5,068,458 to Dales et al., (assigned to Beecham Group, PLC.),issued Nov. 26, 1991; U.S. Pat. No. 5,008,283 to Blackburn et al.(assigned to Pfizer, Inc.), issued Apr. 16, 1991; and U.S. Pat. No.5,006,547 to Loose (assigned to Pfizer), issued Apr. 9, 1991, All of theabove patents are hereby incorporated by reference.

Proton pump inhibitors (PPI) are potent inhibitors of gastric acidsecretion, inhibiting H⁺, K⁺—ATPase, the enzyme involved in the finalstep of hydrogen ion production in the parietal cells. The term protonpump inhibitor includes, but is not limited to, omeprazole,lansoprazole, rabeprazole, pantoprazole and leminoprazole, includingisomers, enantiomers and tautomers thereof, and alkaline salts thereofProton pump inhibitors typically include benzimidazole compounds. Thefollowing patents describe various benzimidazole compounds suitable foruse in the invention described herein: U.S. Pat. No. 4,045,563, U.S.Pat. No. 4,255,431, U.S. Pat. No. 4,359,465, U.S. Pat. No. 4,472,409,U.S. Pat. No. 4,508,905, JP-A-59181277, U.S. Pat. No. 4,628,098, U.S.Pat. No. 4,738,975, U.S. Pat. No. 5,045,321, U.S. Pat. No. 4,786,505,U.S. Pat. No. 4,853,230, U.S. Pat. No. 5,045,552, EP-A-295603, U.S. Pat.No. 5,312,824, EP-A-166287, EP-A-519365, EP5129, EP 174,726, EP 166,287and GB 2,163,747, All of the above patents are hereby incorporated byreference. Proton pump inhibitors, e.g. omeprazole and itspharmaceutically acceptable salts, which are used in accordance with theinvention are known compounds and can be produced by known processes. Incertain preferred embodiments, the proton pump inhibitor is omeprazole,either in racernic mixture or only the (−)enantiomer of omeprazole (i.e.esomeprazole), as set forth in U.S. Pat. No. 5,877,192, herebyincorporated by reference.

Omeprazole is typically administered in a 20 mg dose/day for activeduodenal ulcer for 4-8 weeks; in a 20 mg dose/day for gastro-esophagealreflux disease (GERD) or severe erosive esophagitis for 4-8 weeks; in a20 mg dose/twice a day for treatment of Helicobacter pylori (incombination with other agents); in a 60 mg dose/day for active duodenalulcer for 4-8 weeks and up to 120 mg three times/day, and in a 40 mgdose/day for gastric ulcer for 4-8 weeks. Such dosages are contemplatedto be within the scope of the invention. Thus, in certain embodiments ofthe invention, the amount of proton pump inhibitor which is included inthe dosage form is an amount which is considered to be therapeuticallyeffective, in accordance with the dosages set forth above for a varietyof disease states. In other preferred embodiments of the invention, thedose of proton pump inhibitor is sub-therapeutic. For example, when thedrug is omeprazole, the dosage form may contain from about 0.1 mg toabout 120 mg omeprazole.

Lansoprazole is typically administered about 15-30 mg/day; rabeprazoleis typically administered 20 mg/day and pantoprazole is typicallyadministered 40 mg/day. However, any therapeutic or sub-therapeutic doseof these agents is considered within the scope of the present invention.

The proton pump inhibitor(s) included in the dosage forms of theinvention are preferably protected from contact with acidic gastricjuice, and preferably is transferred without exposure to gastric fluiduntil the dosage form reaches a part of the gastrointestinal tract wherethe pH is near neutral and where rapid absorption of omeprazole canoccur.

In preferred embodiments of the invention, the pharmaceuticalcompositions containing the proton pump inhibitors and NSAIDs set forthherein are administered orally. Such oral dosage forms may contain oneor both of the drugs in immediate or sustained release form. The oraldosage forms may be in the form of tablets, capsules, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,multiparticulate formulations, syrups, elixirs, and the like.

The combination of proton pump inhibitor and a NSAID can be employed inadmixtures with conventional excipients, i.e., pharmaceuticallyacceptable organic or inorganic carrier substances suitable for oral,parenteral, nasal, intravenous, subcutaneous, enteral, or any othersuitable mode of administration, known to the art. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohols, gum arabic, vegetable oils, benzylalcohols, polyethylene glycols, gelate, carbohydrates such as lactose,amylose or starch, magnesium stearate talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure buffers, coloring, flavoring and/oraromatic substances and the like. They can also be combined wheredesired with other active agents, e.g., other analgesic agents. For oralapplication, particularly suitable are tablets, dragees, liquids, drops,suppositories, or capsules, caplets and gelcaps. The compositionsintended for oral use may be prepared according to any method known inthe art and such compositions may contain one or more agents selectedfrom the group consisting of inert, non-toxic pharmaceuticallyexcipients which are suitable for the manufacture of tablets. Suchexcipients include, for example an inert diluent such as lactose;granulating and disintegrating agents such as cornstarch; binding agentssuch as starch; and lubricating agents such as magnesium stearate. Thetablets may be uncoated or they may be coated by known techniques forelegance or to delay the release of the active ingredients. Formulationsfor oral use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert diluent.

Aqueous suspensions containing the above-identified combination of drugsand that mixture have one or more excipients suitable as suspendingagents, for example pharmaceutically acceptable synthetic gums such ashydroxypropylmethylcellulose or natural gums. Oily suspensions may beformulated by suspending the above-identified combination of drugs in avegetable oil or mineral oil. The oily suspensions may contain athickening agent such as beeswax or cetyl alcohol. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed.

As is well known in the art, proton pump inhibitors are susceptible todegradation and/or transformation in acidic and neutral media. Forexample, the half-life of degradation of omeprazole in water solutionsat pH-values less than three is shorter than ten minutes. Thedegradation of proton pump inhibitors is catalyzed by acidic compoundsand is stabilized in mixtures with alkaline compounds. The stability ofthis class of antisecretory compounds is also affected by moisture,heat, organic solvents and to some degree by light. With respect to thestability properties of the proton pump inhibitors, it is preferablethat in an oral solid dosage form they be protected from contact withthe acidic gastric juice and the active substance must be transferred inintact form to that part of the gastrointestinal tract where pH is nearneutral and where rapid absorption of the medication can occur.Formulations which address the degradation of proton pump inhibitors inacidic media are described in U.S. Pat. No. 4,786,505, 5,817,338; and5,798,120, each of which is hereby incorporated by reference, and eachof the described formulations in those patents can be modified toinclude one or more NSAIDs pursuant to the present invention.

One preferred embodiment of the invention is a combinationpharmaceutical composition having two active ingredients, comprising aproton pump inhibitor and a NSAID in a single composition, in which theproton pump inhibitor is in the form of individually enteric coatedsubstrates layered onto an NSAID tablet. The enteric coating layer(s)covering the substrates of the proton pump inhibitor (with or withoutthe NSAID) is preferably sufficient to provide acid resistance to thesubstrates. Preferably, the enteric coating layer covering thesubstrates disintegrates/dissolves rapidly in near neutral or alkalinemedia.

In formulations prepared using multiparticulate substrates comprisingenterically coated proton pump inhibitor, such multiparticulates may bemixed with NSAID (e.g., in particulate or powder form) and thenseparated into unit doses. Alternatively, the enterically coatedsubstrates containing the proton pump inhibitor may thereafter by coatedwith the NSAID (with or without further optional overcoatings aredescribed in more detail below). Alternatively, two separate populationsof substrates may be used, one population of substrates being coatedwith the proton pump inhibitor and thereafter enteric-coated, the otherpopulation of substrates comprising the NSAID. The NSAID-containingsubstrates may comprise inert beads coated with the NSAID, or maycomprise a plurality of immediate release matrices containing the NSAID.Thereafter, requisite amounts of each of the two populations ofsubstrates could be incorporated into tablets, or into gelatin capsules,for example.

In embodiments where the substrates comprise inert pharmaceuticallyacceptable beads, the drug(s) may be mixed with further ingredientsprior to being coated onto the beads. Ingredients include, but are notlimited to, binders, surfactants, fillers, disintegrating agents,alkaline additives or other pharmaceutically acceptable ingredients,alone or in mixtures. Binders include, for example, celluloses such ashydroxypropyl methylcellulose, hydroxypropyl cellulose andcarboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starchesand other pharmaceutically acceptable substances with cohesiveproperties. Suitable surfactants include pharmaceutically acceptablenon-ionic or ionic surfactants. An example of a suitable surfactant issodium lauryl sulfate. The inert beads may be first coated with theproton pump inhibitor, overcoated with an enteric coating, andthereafter coated with the NSAID (with or without further optionalovercoatings are described in more detail below). Alternatively, twoseparate populations of beads may be used, one population of beads beingcoated with the proton pump inhibitor and thereafter enteric-coated, theother population of beads being coating with the NSAID. Thereafter,requisite amounts of each of the two populations of beads could beincorporated into tablets, or into gelatin capsules, for example.

Alternatively, the proton pump inhibitor may be optionally mixed withalkaline compounds and further mixed with suitable ingredients (with orwithout the NSAID) as set forth above and then formulated into thesubstrate. Such substrates may be manufactured viaextrusion/spheronization, balling or compression utilizing differentprocess equipments. The size of the substrates maybe, for example, fromabout 0.1 to about 4 mm, and preferably from about 0.1 to about 2 mm.Alternatively, the substrates may include additional ingredients,optionally comprising the NSAID. Such suitable ingredients includefillers, binders, lubricants, disintegrating agents, surfactants andother pharmaceutically acceptable additives. The alkaline compound maybe selected from substances such as the sodium, potassium, calcium,magnesium and aluminium salts of phosphoric acid, carbonic acid, citricacid or other suitable weak inorganic or organic acids; aluminiumhydroxide/sodium bicarbonate coprecipitate; substances normally used inantacid preparations such as aluminum, calcium and magnesium hydroxides;magnesium oxide or composite substances, such as Al₂O₃.6MgO.CO₂12H₂O,(Mg₆Al₂ (OH)₁₆ CO₃.4H₂O), MgO.Al₂O₃.2SiO₂.nH₂O or similar compounds;organic pH-buffering subst such as trihydroxymethylaminomethane, basicamino acids and their salts or other similar, pharmaceuticallyacceptable pH-buffering substances.

Alternatively, the aforementioned substrate can be prepared by usingspray drying or spray congealing technique.

The proton pump inhibitor omeprazole has an asymmetric centre in thesulfur atom, i.e. exists as two optical isomers (enantiomers). Both thepure enantiomers, racemic mixtures (50% of each enantiomer) and unequalmixtures of the two enantiomers are suitable for the pharmaceuticalformulation according to the present invention. A suitable form ofomeprazole for preparation of multiparticulate dosage forms inaccordance with the invention can be the magnesium salt of omeprazolewith a specific degree of crystallinity and other physical propertiesdisclosed in WO 95/01977, hereby incorporated by reference. Othersuitable forms of the active substance are the sodium, potassium,magnesium and calcium salts of the single enantiomers of omeprazole,especially in their crystalline form described in WO 94/27988, herebyincorporated by reference.

Before applying enteric coating layer(s) onto the substrate, thesubstrates may optionally be covered with one or more separating(intermediate) layers, however, in preferred embodiments, the entericcoating is applied directly onto the proton pump inhibitor without theneed for a separating layer.

Preferably, one or more enteric coating layers are applied onto thesubstrate using a suitable coating technique. The enteric coating layermaterial may be dispersed or dissolved in either water or in suitableorganic solvents. As enteric coating layer polymers one or more,separately or in combination, of the following can be used; e.g.solutions or dispersions of methacrylic acid copolymers, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, cellulose acetate trimellitate, carboxymethylethylcellulose,shellac or other suitable enteric coating layer polymer(s).

The enteric coating layers preferably contain effective amounts ofpharmaceutically acceptable plasticizers to obtain the desiredmechanical properties, such as flexibility and hardness of the entericcoating layers. Such plasticizers are for instance, but not restrictedto, triacetin, citric acid esters, phthalic acid esters, dibutylsebacate, cetyl alcohol, polyethylene glycols, polysorbates or otherplasticizers. The amount of plasticizer is optimized for the particularsituation. The amount of plasticizer is usually above 10% by weight ofthe enteric coating layer polymer(s), preferably 15-50%, and morepreferably 20-50%. Additives such as dispersants, colorants, pigments,polymers e.g. poly(ethylacrylate, methylmethacrylate), anti-tacking andanti-foaming agents may also be included into the enteric coatinglayer(s). Other compounds may be added to increase film thickness and todecrease diffusion of acidic gastric juices into the add susceptiblematerial.

Overcoatings may be applied to the substrates coated as set forth above,e.g., by coating or layering procedures in suitable equipments such ascoating pan, coating granulator or in a fluidized bed apparatus usingwater and/or organic solvents for the coating or layering process.Suitable overcoating materials include sugar, polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and the like. Additivessuch as plasticizers, colorants, pigments, fillers, anti-tacking andanti-static agents, such as for instance magnesium stearate, titaniumdioxide, talc and other additives may also be included into theover-coating layer(s).

The enteric coated substrates may then be mixed with tablet excipients(and with the NSAID in certain embodiments) and compressed into amultiple unit tableted dosage form according to the present invention,or alternatively incorporated as unit doses in appropriately sizedgelatin capsules. Compressed, tablets prepared in accordance with theinvention are optionally covered with a film-formiing agent(s) to obtaina smooth surface of the tablet and further enhance the stability of thetablet during packaging and transport. Such a tablet coating layer mayfurther comprise additives like anti-tacking agents, colorants andpigments or other additives to obtain a tablet of good appearance. Thecompaction process (compression) for formulating the multiple unittableted dosage form must not significantly affect the acid resistanceof the enteric coated substrates. In other words the mechanicalproperties, such as the flexibility and hardness as well as thethickness, of the enteric coating layer(s) must secure that therequirements on enteric coated articles in the United StatesPharmacopeia are accomplished and that the acid resistance does notdecrease more than 10% during the compression of pellets into tablets.

In certain preferred embodiments, where the NSAID is incorporated intothe formulation after the enteric coating of the proton pump inhibitorsubstrates, the addition of the NSAID after the addition of the entericcoating to the substrates allows for rapid release of the NSAID anddelayed release of proton pump inhibitor. The NSAID may be present in anouter coating in a form that does not retard its release, or may beseparately incorporated into the formulation as set forth above.

Optionally soft gelatin capsules can be manufactured by filling acomposition comprising the active ingredients as mentioned above and aknown vegetable oil into capsules. Hard gelatin capsules can also bemanufactured by filling into capsules the tablet, granules or pellets,each comprising an active ingredient as mentioned above, and a solidparticulate carrier such as lactose, sucrose, sorbitol, mannitol, potatostarch, corn starch, amylopectin, a cellulose derivative or gelatin.

It is often considered desirable to administer NSAIDs in sustainedrelease form in order to reduce the number of NSAID doses per day,thereby improving patient compliance and efficacy. Proton pumpinhibitors are generally administered on a once- or twice-a-day basis,and it has not generally been contemplated to incorporated proton pumpinhibitors into a sustained release dosage form. The details of how toachieve slowing or delaying of the release are familiar to the skilledworker on the basis of his expert knowledge. The skilled worker islikewise familiar with suitable ancillary substances and vehicles forthe required dosage forms pharmaceutical formulations). Besides solvent,tablet auxiliary substances and other active ingredient excipients it ispossible to use, for example, tablet-coating compositions, plasticizers,antioxidants, preservatives, and dyes. Where incompatibilities betweenthe active ingredients or between the active ingredients and ancillarysubstances are expected, suitable separating layers are provided whereappropriate (for example in layered or multi-layer tablets).

In certain embodiments in which the NSAID is incorporated into thedosage form in a sustained release form designed to slowly release theNSAID over time, the proton pump inhibitor may be formulated in thedosage form to release via a different mechanism, e.g., via an entericcoating. However, in view of the rationale for administration of theproton pump inhibitors in accordance with the invention (prophylaxis asopposed to treatment of existing disease states), it is contemplatedthat in certain preferred embodiments, the proton pump inhibitor isincorporated into the dosage form in a sustained release state togetherwith the NSAID.

In certain embodiments, the NSAID (and optionally the proton pumpinhibitor) can be formulated as a sustained release oral formulation inany suitable tablet, coated tablet or multiparticulate formulation knownto those skilled in the art. The sustained release dosage form mayoptionally include a sustained released carrier which is incorporatedinto a matrix along with the drug(s), or the sustained release carriercan be applied as a sustained release coating. The sustained releasedosage form may comprise a plurality of substrates which include theNSAID and/or the NSAID and the proton pump inhibitor. The substrates maycomprise matrix spheroids or may comprise inert pharmaceuticallyacceptable beads which are coated with the drug(s). The coated beads maythen be overcoated with a sustained release coating comprising thesustained release carrier. The matrix spheroid may include the sustainedrelease carrier in the matrix itself; or the matrix may comprise anormal release matrix containing the drugs, the matrix having a coatingapplied thereon which comprises the sustained release carrier. In yetother embodiments, the oral solid dosage form comprises a tablet corecontaining the drugs within a normal release matrix, with the tabletcore being coated with a sustained release coating comprising thesustained release carrier. In yet further embodiments, the tabletcontains the drugs within a sustained release matrix comprising thesustained release carrier. In yet further embodiments, the tabletcontains the NSAID within a sustained release matrix and the proton pumpinhibitor coated into the tablet in an enteric coated layer. In yetfurther embodiments, the dosage form comprises a plurality ofmultiparticulates comprising the NSAID in sustained release form (e.g.,prepared in any of the manners set forth above) together with apopulation of a plurality of multiparticulates comprising the protonpump inhibitor in an acid-protected form (e.g., enteric coated).

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. A pH-dependent coating serves torelease the proton pump inhibitor in desired areas of thegastro-intestinal (GI) tract, e.g., the small intestine, such that anabsorption profile is provided which is capable of providing at leastabout twelve hour and preferably up to twenty-four hour relief to apatient. When a pH-independent coating is desired, the coating isdesigned to achieve optimal release regardless of pH-changes in theenvironmental fluid, e.g., the GI tract. It is also possible andpreferable to formulate compositions which release a portion of thedose, preferably the NSAID, in one desired area of the GI tract, e.g.,the stomach, and release the remainder of the dose, preferably theproton pump inhibitor, in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug, preferably the NSAID, is coated over theenteric coat and is released in the stomach, while the remainder,preferably containing the proton pump inhibitor, being protected by theenteric coating, is released further down the gastrointestinal tract.Coatings which are pH-dependent may be used in accordance with thepresent invention, including shellac, cellulose acetate phthalate (CAP),polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulosephthalate, and methacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the proton pump inhibitor (with or withoutthe NSAID) is coated with a hydrophobic material selected from (i) analkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. Thecoating may be applied in the form of an organic or aqueous solution ordispersion. The coating may be applied to obtain a weight gain fromabout 2 to about 25% of the substrate in order to obtain a desiredsustained release profile.

In certain preferred embodiments, the oral dosage form of the presentinvention comprises a compressed matrix comprising the NSAID or a saltthereof and a retardant material in an effective amount to provide acontrolled release of the NSAID for at least about 24 hours; a protonpump inhibitor coated on the surface of the matrix, wherein the protonpump inhibitor is in an amount effective to inhibit gastrointestinalside effects normally associated with oral administration of the NSAID;and an overcoat with a material suitable to prevent contact of saidproton pump inhibitor with acidic gastric juice after oraladministration. Preferably, the NSAID is diclofenac or apharmaceutically acceptable salt thereof and the proton pump inhibitoris omeprazole or a pharmaceutically acceptable salt thereof.

The retardant material which may be included in the matrix with theNSAID can include one or more pharmaceutically acceptable hydrophobicmaterials and/or hydrophilic materials which are capable of impartingcontrolled release of the active agent in accordance with the presentinvention.

The hydrophobic material is preferably selected from the groupconsisting of waxes, alkylcelluloses, acrylic and methacrylic acidpolymers and copolymers, hydrogenated castor oil, hydrogenated vegetableoil, gums, protein derived materials, aliphatic alcohols or mixturesthereof.

In certain embodiments of the present invention, the hydrophobicmaterial is a pharmaceutically acceptable acrylic polymer, including butnot limited to acrylic acid and methacrylic acid copolymers, methylmethacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates,cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid), poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as alkylcelluloses, e.g.methylcellulose or ethylcellulose. In other embodiments, the hydrophobicmaterial is an aliphatic alcohol, e.g. lauryl alcohol, myristyl alcohol,or stearyl alcohol.

An example of a suitable retardant material having hydrophilicproperties is a hydroxyalkylcellulose, e.g.hydroxypropylmethylcellulose.

This list is not meant to be exclusive, and any pharmaceuticallyacceptable hydrophobic material and/or hydrophilic material which arecapable of imparting controlled release of the active agent may be usedin accordance with the present invention.

In addition to the above ingredients, the matrix may also containsuitable quantities of other materials, e.g. diluents, lubricants,binders, granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art. The quantities of theseadditional materials will be sufficient to provide the desired effect tothe desired formulation. Specific examples of pharmaceuticallyacceptable carriers and excipients that may be used to formulate oraldosage forms are described in the Handbook of Pharmaceutical Excipients,American Pharmaceutical Association (1986), incorporated by referenceherein.

A further ingredient which can be added to the matrix is a pH modifyingagent which is defined for purposes of the present invention to mean anysubstance which decreases the ionization of the medicament, whereby therelease of the drug from the matrix and into solution is facilitated.Suitable pH modifying agent are organic acids such as citric acid,succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid orlactic acid.

Prior to coating the matrix with the proton pump inhibitor, the matrixcan be coated with a pharmaceutically acceptable filn-coating, e.g., forstability purposes (e.g., coated with a moisture barrier), etc. Forexample, the matrix may be overcoated with a film coating, preferablycontaining a pigment and a barrier agent, such ashydroxypropylmethylcellulose and/or a polymethylmethacrylate. An exampleof a suitable material which may be used for such a hydrophilic coatingis hydroxypropylmethylcellulose (e.g., Opadry®, commercially availablefrom Colorcon, West Point, Pa.). Any pharmaceutically acceptable mannerknown to those skilled in the art may be used to apply the coatings. Forexample, the coating may be applied using a coating pan or a fluidizedbed. An organic, aqueous or a mixture of an organic and aqueous solventis used for the hydrophobic polymer or enteric coating. Examples ofsuitable organic solvents are, e.g., isopropyl alcohol, ethanol, and thelike, with or without water. Aqueous solvents are preferred for theovercoating procedures.

The proton pump inhibitor is coated onto the tablet. Preferably, asolution of the proton pump inhibitor is spray dried onto the surface ofthe tablet using any spray technique known to those skilled in the art.This coating can also be applied using a coating pan or a fluidized bedusing an organic, aqueous or a mixture of an organic and aqueous solventfor the proton pump inhibitor. Preferably, aqueous solvents arepreferred for the proton pump inhibitor coating.

The material suitable to prevent contact of said proton pump inhibitorwith acidic gastric juice after oral administration is then overcoatedonto the proton pump inhibitor coated matrix. This material preferablycontains an enteric polymer. Examples of suitable enteric polymersinclude cellulose acetate phthalate, hydroxypropylnethylcellulosephthalate, polyvinylacetate phthalate, methacrylic acid copolymer,shellac, hydroxypropylmethylcellulose succinate, cellulose acetatetrimellitate, and mixtures of any of the foregoing. A suitablecommercially available enteric material, for example is sold under thetrademark Eudragit™ L 100-555, as defined above. This coating can bespray coated onto the substrate as previously mentioned with respect tothe other layers of this embodiment of the invention. Preferably, thecoating to prevent contact of said proton pump inhibitor with acidicgastric juice is applied directly over the proton pump inhibitor withoutan intermediate separating layer.

In another preferred embodiment of the invention, the oral solid dosageform comprises a compressed matrix comprising (i) an NSAID or a saltthereof and a retardant material in an effective amount to provide acontrolled release of the NSAID for at least about 24 hours and (ii) aplurality of particles comprising a proton pump inhibitor in asufficient amount to provide an effective dose of the proton pumpinhibitor to inhibit or prevent gastrointestinal side effects associatedwith diclofenac treatment. Preferably, the NSAID is diclofenac or apharmaceutically acceptable salt thereof and the proton pump inhibitoris omeprazole or a pharmaceutically acceptable salt thereof.

The compressed matrix of this embodiment can be prepared in accordancewith the compressed matrix described in the immediately precedingembodiment. For example, the retardant material can be an aliphaticalcohol, such as a stearyl alcohol and can be combined with the NSAID toform a matrix.

The plurality of particles comprising the proton pump inhibitor can bein the form of substrates coated with the proton pump inhibitor and thenovercoated with a material suitable to prevent contact of said protonpump inhibitor with acidic gastric juice after oral administration, e.g.an enteric coating. Preferably, the coating to prevent contact of saidproton pump inhibitor with acidic gastric juice is applied directly overthe proton pump inhibitor without an intermediate separating layer.

In embodiments where the substrates comprise a plurality of inertpharmaceutically acceptable beads, the proton pump inhibitor can bemixed with further ingredients prior to being coated onto the beads.Ingredients include, but are not limited to, binders, surfactants,fillers, disintegrating agents, alkaline additives or otherpharmaceutically acceptable ingredients, alone or in mixtures. Bindersinclude, for example, celluloses such as hydroxypropyl methylcellulose,hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinylpyrrolidone, sugars, starches and other pharmaceutically acceptablesubstances with cohesive properties. Suitable surfactants includepharmaceutically acceptable non-ionic or ionic surfactants. An exampleof a suitable surfactant is Polysorbate-80.

The NSAID matrix and the proton pump inhibitor particles are thenencapsulated in a pharmaceutically acceptable capsule.

In embodiments where the NSAID is included in sustained release form,the amount of NSAID included will generally be based upon a multiple ofthe amount administered in immediate release form, depending of courseupon the dosage frequency. In general, when the proton pump inhibitor isincorporated in sustained release form as well as the NSAID, the amountof proton pump inhibitor will remain within the same limits as set forthabove with respect to enteric release forms.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Preparation of Diclofenac sodium Extended-release/OmeprazoleDelayed-release Tablets, 100/20 mg

The above formulation was prepared by preparing diclofenac extendedrelease (ER) granules and compressing the granules into tablets. Thetablets are were seal coated, followed by spray coating with anomeprazole suspension. The omeprazole coated tablet was then entericcoated, followed by a color coating.

In particular, the ingredients as set forth below in Table 1 weregranulated to form Diclofenac Sodium ER Granules:

TABLE 1 Ingredients % Weight Diclofenac Sodium, USP 45.87 Fumaric Acid,NF 1.01 Cetyl Alcohol, NF 6.01 Stearyl Alcohol, NF 6.01 ColloidalSilicon Dioxide (CAB-O-SIL M-5) 1.01 Compressible Sugar (DI-PAC) 40.09Total 100.00

The Diclofenac Sodium granules were then compressed with MagnesiumStearate to form Diclofenac Sodium ER Tablets, 100 mg (Uncoated). Theseuncoated tablets were then seal coated and drug layered with theingredients set forth in Table 2.

TABLE 2 Ingredients % Weight Diclofenac Sodium ER Tablets, 100 mg(uncoated) 78.596  Omeprazole, USP (micronized) 8.217 Opadry ClearYS-1-7006 2.858 L-Arginine Base, USP/FCC 0.146 Polysorbate 80, NF 0.733D-Mannitol, USP 8.217 Povidone, USP 1.233 Purifed Water, USP* * Total100.000  *Evaporate during the process

For the seal coating, the Opadry Clear was added to the Purified Water,USP and sprayed onto the uncoated tablets. After a 10 minute dryingperiod, an omeprazole suspension with the remaining ingredients weresprayed onto the seal coated tablets to form an immediate release (IR)omeprazole layer.

The Diclofenac Sodium ER/Omeprazole IR tablets, 100/20 mg were thenenteric coated with the ingredients set forth in Table 3, The entericcoating was applied directly onto the immediate release omeprazole layerwithout an intermediate separating layer.

TABLE 3 Ingredients % Weight Diclofenac Sodium ER/Omeprazole DR Tablets90.462  Hydroxypropyl Methylcellulose Phthalate 50, NF 4.637 Talc, USP4.637 Cetyl Alcohol, NF 0.265 Isopropyl Alcohol, USP* * Acetone, NF* *Total 100.000  *Evaporated during the coating process

These enteric coated tablets were then color coated with an aqueoussolution of Opadry White to form the final product.

The dissolution profile of omeprazole from the Diclofenac SodiumER/Omeprazole DR tablets 0.5 M Phosphate buffer medium at a pH 6.8 isset forth in FIG. 1 and Table 4 below:

TABLE 4 Amount Dissolved (% Omeprazole) Time (min) V1 V2 V3 V4 V5 V6Mean % RSD Min. Max  0 0 0 0 0 0 0  0  0  0  0  5 0 0 0 0 0 1  0 245   0 1 10 13 16 13 22 25 20 18 27 13 25 20 86 89 81 82 81 88 85  4 81 89 3092 93 92 90 86 95 91  3 86 95

The dissolution profile of diclofenac from the Diclofenac SodiumER/Omeprazole DR tablets in a 0.5 Phosphate buffer medium at a pH 6.8 isset forth in FIG. 2 and Table 5 below:

TABLE 5 Amount Dissolved (% Diclofenac sodium) Time (Hr) V1 V2 V3 V4 V5V6 Mean % RSD Min. Max 0 0 0 0 0 0 0  0 0  0  0 0.5 7 7 7 7 7 7  7 4  7 7 1 12 12 12 12 12 12 12 3 12 12 2 20 20 20 20 21 21 20 3 20 21 3 27 2727 27 28 28 27 2 27 28 4 33 34 34 35 35 34 34 2 33 35 6 43 43 44 45 4544 44 2 43 45 8 49 49 50 51 50 50 50 2 49 51 12 56 56 57 59 56 57 57 256 59

The tablets were then exposed to accelerated storage conditions of 40°C. and 75% relative humidity for 2 weeks. The dissolution of omeprazoleand diclofenac from the accelerated storage tablets 0.5 M Phosphatebuffer medium at a pH 6.8 showed the formulation to be stable.

EXAMPLE 2 Preparation of Diclofenac sodium ER/Omeprazole DR Capsules,100/20 mg

The above formulation was prepared by preparing diclofenac extendedrelease granules and compressing the granules into tablets, followed bya seal coating. Delayed release enteric coated omeprazole pellets werethen prepared and encapsulated with the extended release diclofenactablet.

In particular, Diclofenac Sodium ER Tablets, 100 mg (Seal Coated)tablets were prepared in accordance with Example 1.

Omeprazole Active Pellets were prepared by coating inert beads with anomeprazole suspension in accordance with the ingredients set forth inTable 6 below:

TABLE 6 Ingredients % Weight Sugar Sphere, NF (18/20) 69.700 Omeprazole,USP (micronized) 14.000 Polysorbate 80, NF  1.250 L-Arginine Base, USP 0.250 D-Mannitol, USP 14.000 Povidone, USP (Plasdone K-90)  0.800Purified Water, USP* * Total 100.000  *Evaporated during the coatingprocess

The omeprazole active pellets were then enteric coated with theingredients set forth in Table 7. The enteric coating was applieddirectly onto the omeprazole pellets without an intermediate separatinglayer.

TABLE 7 Ingredients % Weight Omeprazole Active Pellets 81.00 Hydroxypropyl Methylcellulose Phthalate 55, NF 9.27 Cetyl Alcohol, NF0.46 Talc, USP 9.27 Isopropyl Alcohol, USP* * Acetone, NF* * Total100.00  *Evaporated during the process

A sufficient amount of enteric coated omeprazole pellets to provide 20mg omeprazole were then encapsulated with a Diclofenac Sodium ER sealcoated tablet to form Diclofenac Sodium ER/Omeprazole DR Capsules,100/20 mg.

The dissolution profile of diclofenac from the Diclofenac SodiumER/Omeprazole DR capsules in a 0.5 M Phosphate buffer medium at a pH 6.8is set forth in FIG. 3 and Table 8 below:

TABLE 8 Amount Dissolved (% Diclofenac sodium) Time (Hr) V1 V2 V3 V4 V5V6 Mean % RSD Min. Max 0 0 0 0 0 0 0  0 0  0  0 0.5 4 4 4 4 3 4  4 3  3 4 1 7 8 8 8 7 8  8 2  7  8 2 15 16 16 15 15 16 16 2 15 16 3 23 23 22 2223 24 23 2 22 24 4 29 29 28 28 28 30 29 3 28 30 6 38 38 36 36 36 38 37 336 38 8 44 43 42 42 42 44 43 3 42 44 12 52 51 49 49 49 52 50 3 49 52

The dissolution profile of omeprazole from the Diclofenac SodiumER/Omeprazole DR capsules in a 0.5 M Phosphate buffer medium at a pH 6.8is set forth in FIG. 4 and Table 9 below:

TABLE 9 Amount Dissolved (% Omeprazole) Time (min) V1 V2 V3 V4 V5 V6Mean % RSD Min. Max  0 0 0 0 0 0 0  0 0  0  0  5 3 3 5 6 4 10  5 50   310 10 59 58 66 71 55 71 64 11  55 71 20 86 86 87 89 82 88 86 3 82 89 3087 87 86 89 82 88 87 3 82 89

Capsules were then exposed to accelerated storage conditions of 40° C.and 75% relative humidity for 2 weeks. The dissolution of diclofenacfrom the accelerated storage capsules in a 0.5 M Phosphate buffer mediumat a pH 6.8 showed the formulation to be stable.

EXAMPLES 3-7

In Example 3, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 1. These seal coated tablets are then sprayedwith an aqueous lansoprazole solution or suspension and enteric coatedin accordance with the drug layering and enteric coating procedures ofExample 1. The final dosage form contains 100 mg diclofenac sodium and15 mg lansoprazole.

In Example 4, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 1. These seal coated tablets are then sprayedwith an aqueous pantoprazole solution or suspension and enteric coatedin accordance with the drug layering and enteric coating procedures ofExample 1. The final dosage form contains 100 mg diclofenac sodium and40 mg pantoprazole.

In Example 5, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 1. These seal coated tablets are then sprayedwith an aqueous rabeprazole solution or suspension and enteric coated inaccordance with the drug layering and enteric coating procedures ofExample 1. The final dosage form contains 100 mg diclofenac sodium and20 mg rabeprazole.

In Example 6, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 1. These seal coated tablets are then sprayedwith an aqueous esomeprazole solution or suspension and enteric coatedin accordance with the drug layering and enteric coating procedures ofExample 1. The final dosage form contains 100 mg diclofenac sodium and20 mg esomeprazole.

In Example 7, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 1. These seal coated tablets are then sprayedwith an aqueous (+) omeprazole solution or suspension and enteric coatedin accordance with the drug layering and enteric coating procedures ofExample 1. The final dosage form contains 100 mg diclofenac sodium and20 mg (+) omeprazole.

EXAMPLES 8-12

In Example 8, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 2. Lansoprazole Active Pellets are preparedand enteric coated in accordance with the bead layering and entericcoating procedures of Example 2. A sufficient amount of enteric coatedpellets to provide 15 mg lansoprazole are then encapsulated with theDiclofenac Sodium ER seal coated tablet to form Diclofenac SodiumER/Lansoprazole DR Capsules, 100/15 mg.

In Example 9, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 2. Pantoprazole Active Pellets are preparedand enteric coated in accordance with the bead layering and entericcoating procedures of Example 2. A sufficient amount of enteric coatedpellets to provide 40 mg pantoprazole are then encapsulated with theDiclofenac Sodium ER seal coated tablet to form Diclofenac SodiumER/Pantoprazole DR Capsules, 100/40 mg.

In Example 10, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 2. Rabeprazole Active Pellets are preparedand enteric coated in accordance with the bead layering and entericcoating procedures of Example 2. A sufficient amount of enteric coatedpellets to provide 20 mg rabeprazole are then encapsulated with theDiclofenac Sodium ER seal coated tablet to form Diclofenac SodiumER/Rabeprazole DR Capsules, 100/20 mg.

In Example 11, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 2. Esomeprazole Active Pellets are preparedand enteric coated in accordance with the bead layering and entericcoating procedures of Example 2. A sufficient amount of enteric coatedpellets to provide 20 mg esomeprazole are then encapsulated with theDiclofenac Sodium ER seal coated tablet to form Diclofenac SodiumER/Esomeprazole DR Capsules, 100/20 mg.

In Example 12, Diclofenac Sodium ER Tablets are prepared and seal coatedin accordance with Example 2. (+) Omeprazole Active Pellets are preparedand enteric coated in accordance with the bead layering and entericcoating procedures of Example 2. A sufficient amount of enteric coatedpellets to provide 20 mg (+) omeprazole are then encapsulated with theDiclofenac Sodium ER seal coated tablet to form Diclofenac Sodium ER/(+)omeprazole DR Capsules, 100/20 mg.

In Examples 1 and 2, the specified proton pump inhibitor is in thearginine salt form. Equivalent amounts of other forms of the proton pumpinhibitor such as the free base, pharmaceutically acceptable saltsthereof (e.g., the sodium, potassium, magnesium, calcium and amino acidsalts, or mixtures thereof) or mixtures thereof, can be utilized aswell.

What is claimed is:
 1. A solid oral dosage form comprising: a) adiclofenac extended release tablet and b) an enterically coatedproton-pump inhibitor without a separating layer between the proton pumpinhibitor and the enteric coat; wherein said proton pump inhibitor iscoated onto a plurality of inert beads, and wherein a sufficient amountof proton pump inhibitor enteric coated beads to provide a therapeuticeffect and the diclofenac tablet are contained within a capsule.
 2. Thesolid oral dosage form of claim 1 wherein said proton pump inhibitor iscoated onto the surface of the tablet.
 3. The solid dosage form of claim1 further comprising a film coating over said enteric coat.
 4. The soliddosage form of claim 2 wherein said proton pump inhibitor is selectedfrom the group consisting of omeprazole, lansoprazole, rabeprazole,pantoprazole, leminoprazole, single enantiomers thereof, alkaline saltsthereof and mixtures thereof.
 5. The solid dosage form of claim 4wherein said proton pump inhibitor is omeprazole or a pharmaceuticallyacceptable salt thereof.
 6. A solid oral dosage form comprising: a) adiclofenac extended release tablet and b) an enterically coatedproton-pump inhibitor with a separating layer between the proton pumpinhibitor and the enteric coat; wherein said proton pump inhibitor iscoated onto a plurality of inert beads, and wherein a sufficient amountof proton pump inhibitor enteric coated beads to provide a therapeuticeffect and the diclofenac tablet are contained within a capsule.
 7. Ansolid dosage form for oral administration comprising: a compressedmatrix tablet comprising an NSAID or a pharmaceutically acceptable saltthereof and a retardant material in an effective amount to provide acontrolled release of said NSAID in an amount sufficient to provide atherapeutic effect for at least about 24 hours; and a plurality ofparticles comprising a proton pump inhibitor coated on the surface ofsaid matrix tablet in an amount effective to inhibit gastrointestinalside effects associated with oral administration of said NSAID; saidcoated matrix overcoated with a material suitable to prevent contact ofsaid proton pump inhibitor with acidic gastric juice after oraladministration.
 8. The solid dosage form of claim 1 wherein said protonpump inhibitor is selected from the group consisting of omeprazole,lansoprazole, rabeprazole, pantoprazole, leminoprazole, singleenantiomers thereof, alkaline salts thereof and mixtures thereof.
 9. Thesolid dosage form of claim 8 wherein said proton pump inhibitor isomeprazole or a pharmaceutically acceptable salt thereof.
 10. A soliddosage form for oral administration comprising: a compressed matrixtablet comprising diclofenac or a pharmaceutically acceptable saltthereof and a retardant material in an effective amount to provide acontrolled release of diclofenac in an amount sufficient to provide atherapeutic effect for at least about 24 hours; and a proton pumpinhibitor coated on the surface of said matrix in an amount effective toinhibit gastrointestinal side effects associated with oraladministration of said diclofenac; said coated matrix overcoated with amaterial suitable to prevent contact of said proton pump inhibitor withacidic gastric juice after oral administration.
 11. The solid dosageform of claim 10 wherein said proton pump inhibitor is selected from thegroup consisting of omeprazole, lansoprazole, rabeprazole, pantoprazole,leminoprazole, single enantiomers thereof, alkaline salts thereof andmixtures thereof.
 12. The solid dosage form of claim 11 wherein saidproton pump inhibitor is omeprazole or an alkaline salt thereof.
 13. Thesolid dosage form of claim 12 wherein said omeprazole or alkaline saltthereof is spray coated onto said matrix.
 14. The solid dosage form ofclaim 10 wherein said material suitable to prevent contact of saidproton pump inhibitor with acidic gastric juice is an enteric coating.15. The solid dosage form of claim 14 comprising a film coating or colorcoating over said enteric coating.
 16. The solid dosage form of claim 10wherein said retardant material is an aliphatic alcohol.
 17. The soliddosage form of claim 16 wherein said aliphatic alcohol is selected fromthe group consisting of stearyl alcohol, cetyl alcohol and mixturesthereof.
 18. The solid dosage form of claim 10 wherein said diclofenacand said retardant material are in granular form prior to compression.19. The oral dosage form of claim 10 further comprising a film coatingbetween said matrix and said proton pump inhibitor.
 20. A solid dosageform for oral administration comprising: a compressed matrix tabletcomprising diclofenac or a pharmaceutically acceptable salt thereof anda retardant material in an effective amount to provide a controlledrelease of diclofenac in an amount sufficient to provide a therapeuticeffect for at least about 24 hours; and a plurality of particlescomprising a proton pump inhibitor coated onto the surface of aplurality of inert beads and overcoated with a material suitable toprevent contact of said proton pump inhibitor with acidic gastric juiceafter oral administration; said dosage form containing a sufficientamount of said particles to provide an effective dose of said protonpump inhibitor to inhibit gastrointestinal side effects associated withoral administration of said diclofenac; said compressed matrix and saiddose of proton pump inhibitor contained within a capsule.
 21. The soliddosage form of claim 20 wherein said proton pump inhibitor is selectedfrom the group consisting of omeprazole, lansoprazole, rabeprazole,pantoprazole, leminoprazole, single enantiomers thereof, alkaline saltsthereof and mixtures thereof.
 22. The solid dosage form of claim 21wherein said proton pump inhibitor is omeprazole or a pharmaceuticallyacceptable salt thereof.
 23. The dosage form of claim 20 wherein saidmaterial suitable to prevent contact of said omeprazole orpharmaceutically acceptable salt thereof with acidic gastric juice is anenteric material.
 24. The solid dosage form of claim 20 wherein saidretardant material is an aliphatic alcohol.
 25. The solid dosage form ofclaim 24 wherein said aliphatic alcohol is selected from the groupconsisting of stearyl alcohol, cetyl alcohol and mixtures thereof. 26.The solid dosage form of claim 20 wherein said diclofenac and saidretardant material are in granular form prior to compression.
 27. Amethod of treating patients with diclofenac comprising administering thesolid dosage form of claim
 1. 28. A method of treating patients withdiclofenac comprising administering the solid dosage form of claim 10.29. A method of treating patients with diclofenac comprisingadministering the solid dosage form of claim
 20. 30. A solid dosage formfor oral administration comprising: a compressed matrix tabletcomprising an NSAID or a pharmaceutically acceptable salt thereof and aretardant material in an effective amount to provide a controlledrelease of said NSAID in an amount sufficient to provide a therapeuticeffect for at least about 24 hours; and a plurality of particlescomprising a proton pump inhibitor coated onto the surface of aplurality of inert beads and overcoated with a material suitable toprevent contact of said proton pump inhibitor with acidic gastric juiceafter oral administration; said dosage form containing a sufficientamount of said particles to provide an effective dose of said protonpump inhibitor to inhibit gastrointestinal side effects associated withoral administration of said diclofenac; said compressed matrix and saiddose of particles contained within a capsule.
 31. The dosage form ofclaim 7, wherein the NSAID is selected from the group consisting ofsalicylates, indomethacin, flurbiprofen, diclofenac, ketorolac,naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone,tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone,phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone,benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole,fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen,ketoprofen, meclofenamic acid, mefenamic acid, niflumic acid,phenacetin, salidifamides, sulindac, suprofen, tolmetin,pharmaceutically acceptable salts thereof, and mixtures thereof.
 32. Thedosage form of claim 7, wherein the proton pump inhibitor is selectedfrom the group consisting of omeprazole, lansoprazole, rabeprazole,pantoprazole, leminoprazole, single enantiomers thereof, alkaline saltsthereof, and mixtures thereof.
 33. The dosage form of claim 30, whereinthe NSAID is selected from the group consisting of salicylates,indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac,antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone,clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome,cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl,flufenamic acid, glaphenine, indoprofen, ketoprofen, meclofenamic acid,mefenamic acid, niflumic acid, phenacetin, salidifamides, sulindac,suprofen, tolmetin, pharmaceutically acceptable salts thereof, andmixtures thereof.
 34. The dosage form of claim 30, wherein the protonpump inhibitor is selected from the group consisting of omeprazole,lansoprazole, rabeprazole, pantoprazole, leminoprazole, singleenantiomers thereof, alkaline salts thereof, and mixtures thereof.